Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia in Caucasians (see Pandolfo (1999) Semin. Neurol. 19:311). Individuals with FRDA have a deficiency of the mRNA encoding frataxin, a highly conserved 210 amino acid nuclear-encoded, mitochondrial protein that is thought to be involved in iron homeostasis, storage and transfer of iron-sulfur clusters to partner proteins such as aconitase (see Bulteau et al. (2004) Science 305:242; Seznec et al. (2005) Hum. Mol. Genet. 14:463; Calabrese et al. (2005) J. Neurol. Sci. 233:145).
Frataxin insufficiency leads to progressive spinocerebellar neurodegeneration resulting in gait and hand in-coordination, slurred speech, muscle weakness and sensory loss with extraneural scoliosis, cardiomyopathy and diabetes. Generally within 15 to 20 years after the first appearance of symptoms, an affected individual is confined to a wheelchair and in later stages, become completely incapacitated. Most affected individuals die in early adulthood of heart disease. Although antioxidant- and iron-chelator-based strategies have been used to treat FRDA, these strategies only treat the symptoms of the disease and not the cause, i.e. frataxin deficiency. Therefore, there is a need to develop molecules that could restore frataxin protein expression for the treatment of a neurological condition such as FRDA.
In addition, the DNA abnormality found in 98% of FRDA patients is the unstable hyper-expansion of a GAA triplet repeat in the first intron of the frataxin gene (see Campuzano et al., Science 271:1423 (1996)). Triplet repeat expansion in genomic DNA is associated with many other neurodegenerative and neuromuscular diseases including, without limitation, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy's disease, spinal and bulbar muscular atrophy and Alzheimer's disease. Triplet repeat expansion may cause disease by altering gene expression. For example, in Huntington's disease, the spinocerebellar ataxias, fragile X syndrome and myotonic dystrophy, expanded repeats lead to gene silencing. Therefore, there is a need to develop molecules that could restore the normal function of genes in neurological diseases.